Dataset Information

Reconstruction and signal propagation analysis of the Syk signaling network in breast cancer cells.

ABSTRACT: The ability to build in-depth cell signaling networks from vast experimental data is a key objective of computational biology. The spleen tyrosine kinase (Syk) protein, a well-characterized key player in immune cell signaling, was surprisingly first shown by our group to exhibit an onco-suppressive function in mammary epithelial cells and corroborated by many other studies, but the molecular mechanisms of this function remain largely unsolved. Based on existing proteomic data, we report here the generation of an interaction-based network of signaling pathways controlled by Syk in breast cancer cells. Pathway enrichment of the Syk targets previously identified by quantitative phospho-proteomics indicated that Syk is engaged in cell adhesion, motility, growth and death. Using the components and interactions of these pathways, we bootstrapped the reconstruction of a comprehensive network covering Syk signaling in breast cancer cells. To generate in silico hypotheses on Syk signaling propagation, we developed a method allowing to rank paths between Syk and its targets. We first annotated the network according to experimental datasets. We then combined shortest path computation with random walk processes to estimate the importance of individual interactions and selected biologically relevant pathways in the network. Molecular and cell biology experiments allowed to distinguish candidate mechanisms that underlie the impact of Syk on the regulation of cortactin and ezrin, both involved in actin-mediated cell adhesion and motility. The Syk network was further completed with the results of our biological validation experiments. The resulting Syk signaling sub-networks can be explored via an online visualization platform.

SUBMITTER: Naldi A

PROVIDER: S-EPMC5376343 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Publications

Reconstruction and signal propagation analysis of the Syk signaling network in breast cancer cells.

Naldi Aurélien A Larive Romain M RM Czerwinska Urszula U Urbach Serge S Montcourrier Philippe P Roy Christian C Solassol Jérôme J Freiss Gilles G Coopman Peter J PJ Radulescu Ovidiu O

PLoS computational biology 20170317 3

The ability to build in-depth cell signaling networks from vast experimental data is a key objective of computational biology. The spleen tyrosine kinase (Syk) protein, a well-characterized key player in immune cell signaling, was surprisingly first shown by our group to exhibit an onco-suppressive function in mammary epithelial cells and corroborated by many other studies, but the molecular mechanisms of this function remain largely unsolved. Based on existing proteomic data, we report here the ...[more]

PMID: 28306714

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Project description:The mechanisms underlying an effective propagation of high intensity information over a background of irregular firing and response latency in cognitive processes remain unclear. Here we propose a SSCCPI circuit to address this issue. We hypothesize that when a high-intensity thalamic input triggers synchronous spike events (SSEs), dense spikes are scattered to many receiving neurons within a cortical column in layer IV, many sparse spike trains are propagated in parallel along minicolumns at a substantially high speed and finally integrated into an output spike train toward or in layer Va. We derive the sufficient conditions for an effective (fast, reliable, and precise) SSCCPI circuit: (i) SSEs are asynchronous (near synchronous); (ii) cortical columns prevent both repeatedly triggering SSEs and incorrectly synaptic connections between adjacent columns; and (iii) the propagator in interneurons is temporally complete fidelity and reliable. We encode the membrane potential responses to stimuli using the non-linear autoregressive integrated process derived by applying Newton's second law to stochastic resilience systems. We introduce a multithreshold decoder to correct encoding errors. Evidence supporting an effective SSCCPI circuit includes that for the condition, (i) time delay enhances SSEs, suggesting that response latency induces SSEs in high-intensity stimuli; irregular firing causes asynchronous SSEs; asynchronous SSEs relate to healthy neurons; and rigorous SSEs relate to brain disorders. For the condition (ii) neurons within a given minicolumn are stereotypically interconnected in the vertical dimension, which prevents repeated triggering SSEs and ensures signal parallel propagation; columnar segregation avoids incorrect synaptic connections between adjacent columns; and signal propagation across layers overwhelmingly prefers columnar direction. For the condition (iii), accumulating experimental evidence supports temporal transfer precision with millisecond fidelity and reliability in interneurons; homeostasis supports a stable fixed-point encoder by regulating changes to synaptic size, synaptic strength, and ion channel function in the membrane; together all-or-none modulation, active backpropagation, additive effects of graded potentials, and response variability functionally support the multithreshold decoder; our simulations demonstrate that the encoder-decoder is temporally complete fidelity and reliable in special intervals contained within the stable fixed-point range. Hence, the SSCCPI circuit provides a possible mechanism of effective signal propagation in cortical networks.

Dataset Information

Reconstruction and signal propagation analysis of the Syk signaling network in breast cancer cells.

Publications

Reconstruction and signal propagation analysis of the Syk signaling network in breast cancer cells.

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